Baclofen: A Patient Case Related to Medicinal Chemistry and Drug Design Between GABA B Receptors and Baclofen
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RN, who was 55 year old male, was admitted to the ED after being ejected from his vehicle following a car accident. Upon admission to the hospital, it was discovered he had suffered a scapular and thoracic spine fracture, ultimately resulting in spinal shock. Due to the trauma he experienced from the accident, the patient developed severe muscle spasticity and pain. The patient was started on the maximum daily dose of 80 mg of baclofen by mouth for the spasticity in addition to fentanyl and oxycodone to manage his pain. The pharmacist on staff closely monitored the patient for signs and symptoms of CNS depression and adjusted doses of therapies as needed.
Spinal shock is a major cause of muscle spasticity, which leads to rigid muscles and intense pain. GABAB receptor agonists, such as baclofen, are common treatment options for muscle spasticity because they are effective in reducing excessive autonomic muscle tone from the central nervous system (CNS) and, thus, reduce muscle spasticity. The treatment for long term pain management following such traumas, like this patient experienced, often includes opioid analgesic medications as well. Providers prescribing both GABAB agonists with opioid analgesics should be cautious in doing so due to severe side effects from concomitant use of these CNS-affecting drugs. Some of these severe effects include respiratory depression, sedation, and low heart rate.
The molecule of baclofen in the second figure highlights the important amine and carboxylic acid (in deprotonated form) functional groups that interact with the 6 main amino acids found in the active site of the GABAB receptor. The amino acids that interact with these two polar regions on the molecule are: Glutamate-349 and Tryptophan-278, Histidine-170, Tyrosine-250, Serine-130, and Serine-153 (refer to 'Baclofen with Amino Acids' image). The amine group on baclofen interacts with Histidine-170, Glutamate-349, and Tryptophan-278 while the lone electron pairs on the two carboxylic oxygen atoms interact with the two Serines and Tyrosine-250. Each one of these amino acids binds to the baclofen molecule via hydrogen bonds. Two of the protons on the amine interact with the double bonded nitrogen in the imidazole ring of Histidine-170 and the nucleophilic oxygen in Glutamate-349. The Serines form multiple hydrogen bonds with the baclofen molecule's two lone pairs off the carboxylic acid, but Tyrosine-250 only forms one bond to it. The phenyl groups on Tyrosine-250 and Tryptophan-278 also interact with the molecule, but mostly via van der Waals hydrophobic interactions in the active site. The amino acids Tyrosine-250, Histidine-170, and Serine-130 only bind baclofen via hydrogen bonds (refer to 'Baclofen with Amino Acids' image).
As for the β-chlorphenyl group in the baclofen molecule, it is the region of the molecule that participates in the hydrophobic association with two of the amino acids in the active site. Specifically, the β-chlorophenol ring interacts with the Tyrosine-250 and the Tryptophan-278 ring structures to create ring stacking. The indole ring of Tryptophan-278 is flipped around to accommodate the β-chlorophenol ring substituent of baclofen. This flip allows the formation of the aromatic ring stacking, which creates an attractive, hydrophobic interaction between these two amino acids and the baclofen molecule.1
As previously described, baclofen is a skeletal muscle relaxant that selectively binds to the GABAB receptor. Although not fully proven, its proposed mechanism of action is to utilize the GABAB's functionality of moving potassium out of the cell in order to hyperpolarize neurons. This inhibits the cell's ability to fire an action potential and causes the skeletal muscle to contract. As for fentanyl, it's a potent opioid used for the management of pain and its mechanism of action is to inhibit the mu- and kappa- opioid receptors in the spinal cord and CNS.5 This medication uses a similar strategy to baclofen, but by ultimately blocking pain signals via hyperpolarizing neurons and causing potassium efflux using N-type voltage gated calcium channels. Oxycodone is also an opioid with the same mechanism of action as fentanyl, but has a heavier influence on the mu- receptor.6 Unlike fentanyl, it is a traditional opioid, which means it contains a phenanthrene ring in its chemical structure. Both fentanyl and oxycodone affect the perception of pain and the emotional response it elicits and that's the reason why these medications cause feelings of euphoria along with the analgesia. The problem is that the overuse of these medications and those similar to them can potentially lead to physical dependence.
Going back to the patient case, in addition to being prescribed baclofen 80 mg by mouth daily, RN was also started on a fentanyl 50 mcg transdermal patch every 72 hours and oxycodone IR 5 mg tablet every 3 hours as needed for pain therapy. The concomitant use of opiate agonists with baclofen can lead to Opioid Induced Respiratory Depression (OIRD).7 OIRD is a life threatening consequence that results when the ventilation process of respiration is decreased by the effect of the opioid medications on the mu- receptor of respiratory neurons. This can substantially decrease the ability to remove CO2 from the body in exchange for vital oxygen. OIRD is one of the most notable side effects that can occur when these medications are used concomitantly, and have the ability to lower the CNS's control of constitutive functions due to pharmacodynamic effects. Other possible signs of CNS depression are ataxia, confusion, and weakness. Baclofen uses the ability to move potassium from inside and outside of a neuron in the CNS in order to prevent its usual action, so baclofen is also considered a CNS depressant. Thus, patients need to be monitored when baclofen is used concomitantly with opioids since it has the potential to enhance this CNS depressant effect. Ideally, if baclofen only worked in the periphery, these CNS effects could be more easily avoided.
Changing a molecular property of baclofen could be a way to limit the potential CNS effects that these interactions increase risk for. One way to do this is to make baclofen a more specific substrate for P-Glycoprotein (PGP), which would affect its movement through the blood brain barrier. Being a substrate for PGP would potentially help eliminate it from the brain easier, leading to lower risk for severe CNS effects, especially when using concomitant drug therapy. Another potential change could be to make baclofen a more polar molecule, which would keep it from penetrating the brain via the blood brain barrier since polar molecules have a more difficult time crossing it based on their molecular properties.
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